| First Author | Hacke K | Year | 2012 |
| Journal | Exp Hematol | Volume | 40 |
| Issue | 1 | Pages | 3-13.e3 |
| PubMed ID | 22001673 | Mgi Jnum | J:191414 |
| Mgi Id | MGI:5461651 | Doi | 10.1016/j.exphem.2011.09.009 |
| Citation | Hacke K, et al. (2012) Combined preconditioning and in vivo chemoselection with 6-thioguanine alone achieves highly efficient reconstitution of normal hematopoiesis with HPRT-deficient bone marrow. Exp Hematol 40(1):3-13.e3 |
| abstractText | Purine analogs such as 6-thioguanine (6TG) cause myelotoxicity upon conversion into nucleotides by hypoxanthine-guanine phosphoribosyltransferase (HPRT). Here we have developed a novel and highly efficient strategy employing 6TG as a single agent for both conditioning and in vivo chemoselection of HPRT-deficient hematopoietic stem cells. The dose-response and time course of 6TG myelotoxicity were first compared in HPRT wild-type mice and HPRT-deficient transgenic mice. Dosage and schedule parameters were optimized to employ 6TG for myelosuppressive conditioning, immediately followed by in vivo chemoselection of HPRT-deficient transgenic donor bone marrow (BM) transplanted into syngeneic HPRT wild-type recipients. At appropriate doses, 6TG induced selective myelotoxicity without any adverse effects on extrahematopoietic tissues in HPRT wild-type mice, while hematopoietic stem cells deficient in HPRT activity were highly resistant to its cytotoxic effects. Combined 6TG conditioning and post-transplantation chemoselection consistently achieved approximately 95% engraftment of HPRT-deficient donor BM, with low overall toxicity. Long-term reconstitution of immunophenotypically normal BM was achieved in both primary and secondary recipients. Our results provide proof-of-concept that single-agent 6TG can be used for both myelosuppressive conditioning without requiring irradiation and for in vivo chemoselection of HPRT-deficient donor cells. Our results show that by applying the myelosuppressive effects of 6TG both before (as conditioning) and after transplantation (as chemoselection), highly efficient engraftment of HPRT-deficient hematopoietic stem cells can be achieved. |
